期刊
CELL REPORTS
卷 8, 期 6, 页码 1704-1713出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.08.033
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资金
- U.S. Department of Energy [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- NIH [R01GM69090, R01CA134519]
- ACS research scholar grant [118970]
- Brewster Foundation
- Charlotte Elizabeth Procter Fellowship
- NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]
Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.
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